The present invention relates to novel quinoxaline compounds useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutical carrier, and to pharmaceutical methods of treatment. The compounds of the present invention are Interleukin-8 (IL-8) receptor antagonists. More particularly, the compounds of the present invention are useful in the treatment of a chemokine-mediated disease wherein the chemokine binds to an IL-8a (CXCR1) or b (CXCR2) receptor such as, for example, a chemokine-mediated disease selected from psoriasis, or atopic dermatitis, tumor growth and angiogenesis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer""s disease, graft versus host reaction, allograft rejections, or allergic diseases.
IL-8 is a 72 amino acid protein which is a member of the superfamily of leukocyte chemoattractant proteins which have been referred to as intercrines, C-X-C or C-C cytokines or, more recently as chemokines (Oppenheim J. J. et al., xe2x80x9cProperties of the novel proinflammatory supergene xe2x80x9cintercrinexe2x80x9d cytokine family.xe2x80x9d Annu. Rev. Immunol., 1991;9:617-648). Many members of the chemokine family appear to be involved in the inflammatory process and in the trafficking of leukocytes. The chemokine superfamily is composed of two branches: the xcex1- and the xcex2-chemokines. The xcex1-chemokine branch includes IL-8, neutrophil activating peptide-2 (NAP-2), melanoma growth stimulatory activity (MGSA/gro or GROxcex1), and ENA-78, all of which have attracting and activating effects predominantly on neutrophils. This branch also includes PF4, xcex2-thromboglobulin, and CTAPIII, which do not affect neutrophils.
IL-8 was originally identified by its ability to both attract and activate polymorphonuclear leukocytes (neutrophils) and has now been shown to be rapidly induced in a wide variety of cell and tissue types in response to pro-inflammatory cytokines such as IL-1b or TNFxcex1. Additionally, there is data demonstrating high systemic levels of IL-8 in certain neutrophil-mediated inflammatory diseases, suggesting the IL-8 and closely related factors may be the principal endogenous mediators of neutrophil activation. Many reports have been published regarding disorders in which high levels of IL-8 have been measured, and include rheumatoid arthritis, septic shock, asthma, cystic fibrosis, myocardial infarction, and psoriasis (Baggiolini et al., FEBS Lett, 1992;307:97; Miller et al., Crit. Rev. Immunol., 1992;12:17. Oppenhein et al., Annu. Rev. Immunol, 1991;9:617; Seitz et al., J. Clin. Invest., 1991;87:463; Miller et al., Am. Rev. Respir. Dis., 1992;146:427; Donnely et al., Lancet, 1993;341:643). Strong in vivo evidence indicating a central role of IL-8 in the pathology related to lung ischemia/reperfusion has recently been published (Sekido N., Mukaida N. et al., xe2x80x9cPrevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8.xe2x80x9d Nature, 1993;365(6447):654-7 Issn: 0028-0836). A monoclonal antibody to rabbit IL-8, capable of blocking the in vitro neutrophil chemotactic activity of IL-8, prevented tissue damage in the rabbit lung normally resulting from lung ischemia/reperfusion. More recently, another study has shown beneficial effects of an IL-8 neutralizing antibody in an endotoxin-induced pleurisy model in rabbit (Broaddus V. C., Boylan A. M. et al., xe2x80x9cNeutralization of IL-8 inhibits neutrophil influx in a rabbit model of endotoxin-induced pleurisy,xe2x80x9d J. Immunol., 1994;152(6):2960-2967). There were also reports indicating similar beneficial effects with IL-8 neutralizing antibodies in animal models of dermatitis, joint arthritis, and glomerulonephritis. Additionally, knockout mice have been generated in which the apparent mouse homologue of the IL-8R (closer to IL-8RB) was deleted by homologous recombination (Cacalano G., Lee J. et al., xe2x80x9cNeutrophil and b cell expansion in mice that lack the murine IL-8 receptor homolog,xe2x80x9d Science, 1994;265(5172):682-4 Issn: 0036-8075). Although these mice appear healthy, their neutrophils are greatly impaired, as compared to wild-type mice, in their ability to migrate to the peritoneum in response to intraperitoneal thioglycollate injection. All of these results suggest that IL-8 is an important mediator of neutrophil migration and activity in some inflammatory settings, and that a small molecule antagonist to the receptors for IL-8 should prove to be an effective treatment for some inflammatory pathologies and has the potential to be a broadly useful anti-inflammatory agent. Also, there have been reports that IL-8 is an important cytokine involved in tumor growth and angiogenesis in a variety of malignancies (Hebert et al., Cancer Invest., 1993;11:743 and Richards et al., American Journal of Surgery, 1997;174:507).
We have identified a series of quinoxalines that are IL-8 receptor antagonists and which can additionally be used in psoriasis, or atopic dermatitis, disease associated with pathological angiogenesis (i.e. cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer""s disease, graft versus host reaction, allograft rejections, or allergic diseases.
Accordingly, a first aspect of the present invention is a compound of Formula I 
wherein A is selected from the group consisting of: 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl-SO2xe2x80x94,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein
R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, xe2x80x94(CH2)mxe2x80x94OH, or
R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
wherein n is zero or an integer of 1 and R7 and R8 are
each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, and 
xe2x80x83wherein o is an integer of 1 or 2, and R9 is hydrogen or alkyl; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R14 is hydrogen, alkyl, aryl, or aralkyl, and R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R14 are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 is as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
halogen, or
alkoxy, with the proviso
that when A is 
xe2x80x83wherein R3 is hydrogen, methyl, or
chloro, R1 is not 
xe2x80x83wherein R3 is hydrogen; and
R2 is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen,
alkyl, or
aralkyl, 
xe2x80x83wherein n, R5, and R6 are as defined above, 
xe2x80x83wherein R5, R6, and m are as defined above, 
xe2x80x83wherein R12 and R12a are each independently the same or different and are hydrogen, alkyl, or aryl, or taken together can form a 5- to 7-membered ring, and
R13 is hydrogen or alkyl, and
m is as defined above, 
xe2x80x83wherein m, R12, R12a, and R13 are as defined above, 
xe2x80x83wherein R9 and m are as defined above, 
xe2x80x83wherein R9 and m are as defined above, 
xe2x80x83wherein m and o are as defined above, 
xe2x80x83wherein n, o, R5, and R6 are as defined above, 
xe2x80x83wherein n and R9 are as defined above, 
xe2x80x83wherein n is as defined above, 
xe2x80x83wherein n is as defined above, 
xe2x80x83wherein m is as defined above, or
R10 and R11 when taken together can form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above;
or a pharmaceutically acceptable salt thereof.
A second aspect of the present invention is a method of treating a chemokine-mediated disease state, wherein the chemokine binds to an IL-8a (CXCR1) or b (CXCR2) receptor in a mammal, which comprises administering to said mammal an effective amount of compound of Formula II 
wherein A is selected from the group consisting of: 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl-SO2xe2x80x94,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are each the same or different and are hydrogen,
alkyl, cycloalkyl, acetyl, xe2x80x94(CH2)mxe2x80x94OH, or
R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein o is an integer of 1 or 2, and R9 is hydrogen or alkyl; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R14 is hydrogen, alkyl, aryl, or aralkyl, and R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R14 are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 is as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
alkyl,
halogen,
alkoxy,
xe2x80x94OR4 wherein R4 is as defined above, or 
xe2x80x83wherein R7, R8, and n are as defined above; and
R2a is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen,
alkyl, or
aralkyl, and 
xe2x80x83wherein n, R5, and R6 are as defined above, 
xe2x80x83wherein R5, R6, and m are as defined above, 
xe2x80x83wherein R12 and R12a are each independently the same or different and are
hydrogen,
alkyl, or
aryl, or taken together can form a 5- to 7-membered ring, and
R13 is hydrogen or alkyl, and
m is as defined above, 
xe2x80x83wherein m, R12, R12a, and R13 are as defined above, 
xe2x80x83wherein R9 and m are as defined above, 
xe2x80x83wherein R9 and m are as defined above, 
xe2x80x83wherein m and o are as defined above, 
xe2x80x83wherein n, o, R5, and R6 are as defined above, 
xe2x80x83wherein n and R9 are as defined above, 
xe2x80x83wherein n is as defined above, 
xe2x80x83wherein n is as defined above, 
xe2x80x83wherein m is as defined above, or
R10 and R11 when taken together can form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above;
or a pharmaceutically acceptable salt thereof.
As inhibitors of chemokine-mediated diseases, the compounds of Formula I and II can be used as agent for treating psoriasis, or atopic dermatitis, disease associated with pathological angiogenesis (i.e. cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer""s disease, graft versus host reaction, allograft rejections, or allergic diseases.
A still further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a compound of Formula I or Formula II in unit dosage form in the treatment methods mentioned above. Finally, the present invention is directed to methods for production of compounds of Formula I or Formula II.
In the compounds of Formula I or II, the term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 8 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a saturated hydrocarbon ring which contains from 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d and xe2x80x9cthioalkoxyxe2x80x9d are O-alkyl or S-alkyl of from 1 to 6 carbon atoms as defined above for xe2x80x9calkylxe2x80x9d.
The term xe2x80x9carylxe2x80x9d means an aromatic radical which is a phenyl group, a phenyl group substituted by 1 to 4 substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, SO3H, CHO, 
as defined above for alkyl, 
as defined above for alkyl, 
as defined above for alkyl, xe2x80x94(CH2)nxe2x80x94NH2 wherein n is an integer of 1 to 5, xe2x80x94(CH2)nxe2x80x94NH-alkyl as defined above for alkyl and n, xe2x80x94(CH2)nxe2x80x94N(alkyl)2 as defined above for alkyl and n.
The term xe2x80x9cheteroarylxe2x80x9d means a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridinyl, 3-, 4-, or 5-pyridazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, N-formyl-2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]furanyl, or 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, unsubstituted or substituted by one to three substituents selected from alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined above for alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, SO3H, CHO, 
as defined above for alkyl, 
as defined above for alkyl, 
as defined above for alkyl, xe2x80x94(CH2)nxe2x80x94NH2 wherein n is an integer of 1 to 5, xe2x80x94(CH2)nxe2x80x94NH-alkyl as defined above for alkyl and n, xe2x80x94(CH2)nxe2x80x94N(alkyl)2 as defined above for alkyl and n.
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d means an aromatic radical attached to an alkyl radical wherein xe2x80x9carylxe2x80x9d and xe2x80x9calkylxe2x80x9d are as defined above, for example, benzyl, fluorenylmethyl, and the like.
The term xe2x80x9c5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4xe2x80x9d includes, for example, pyrrolidine, pyrrazolidine, imidazolidine, oxazolidine, piperidine, piperazine, morpholine, homopiperidine, and the like. The carbon atoms of the above 5- to 7-membered ring may be substituted independently by alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxyalkyl, alkylcarboxyalkyl, thio, thioalkyl, alkylthioalkyl, hydroxy, hydroxyalkyl, alkoxy, or alkoxyalkyl.
In the compounds of Formula I or II, any unsubstituted carbon atoms of a bicyclic or tricyclic heteroaromatic moiety at R1 or R1a may be substituted by R3, R3a, or R3b.
xe2x80x9cHalogenxe2x80x9d is fluorine, chlorine, bromine, or iodine.
Some of the compounds of Formula I or II are capable of further forming both pharmaceutically acceptable acid addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I or II include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al, xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharma Sci., 1977;66:1).
The acid addition salts of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharma Sci., 1977;66:1).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R(D) or S(L) configuration. The present invention includes all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
A preferred compound of Formula I in the first aspect of the present invention is one wherein A is selected from the group consisting of: 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are each the same or different and are hydrogen,
alkyl, cycloalkyl, acetyl, or
R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, or 
xe2x80x83wherein R3 and R3a are as defined above; 
xe2x80x83wherein R3, R3a and R3b are as defined above, 
xe2x80x83wherein R3, R3a and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, halogen, or
alkoxy; and
R2 is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, and R6 are as defined above, or 
xe2x80x83wherein n, R5, and R6 are as defined above.
A more preferred compound of Formula I in the first aspect of the present invention is one wherein A is 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, or
R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, or 
xe2x80x83wherein R3 and R3a are as defined above; and
R2 is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, and R6 are as defined above, or 
xe2x80x83wherein n, R5, and R6 are as defined above.
Another more preferred compound of Formula I in the first aspect of the present invention is one wherein A is 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
heteroaryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, or
R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, or 
xe2x80x83wherein R3 and R3a are as defined above; and
R2is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, and R6 are as defined above, or 
xe2x80x83wherein n, R5, and R6 are as defined above.
A most preferred compound of Formula I in the first aspect of the present invention is one wherein A is 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein
R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 an m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, or 
xe2x80x83wherein R3, R3a, and R3b are as defined above; and 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, and R6 are as defined above, or 
xe2x80x83wherein n, R5, R6 are as defined above.
Particularly valuable in the first aspect of the present invention is a compound selected from the group consisting of:
N-(1-Azabicyclo[2.2.2]octan-3-yl)-3-(2-pyridinyl)-2-quinoxalinamine;
N-[3-(1H-Imidazol-1-yl)propyl]-3-(2-pyridinyl)-2-quinoxalinamine;
N-[2-(1-Methyl-2-pyrrolidinyl)ethyl]-3-(2-pyridinyl)-2-quinoxalinamine;
1-[3-[[3-Pyridinyl)-2-quinoxalinamine]amino]propyl]-2-pyrrolidinone;
N-[4-(4-Morpholinyl)phenyl]-3-(2-pyridinyl)-2-quinoxalinamine;
N-(4-Piperidinylmethyl)-3-(2-pyridinyl)-2-quinoxalinamine;
N-[4-(Dimethylamino)phenyl]-3-(2-pyridinyl)-2-quinoxalinamine;
N-Methyl-N-[4-[[3-(2-pyridinyl)-2-quinoxalinyl]amino]phenyl]-acetamide;
N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethylcyclohexane-1,4-diamine;
N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)cyclohexane-1,4-diamine;
2-[1,4xe2x80x2]Bipiperidinyl-1xe2x80x2-yl-6,7-dichloro-3-pyridin-2-yl-quinoxaline;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(4-diethylaminomethylphenyl)-amine;
Nxe2x80x2-(6,7-Dichloro-3-furan-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
Nxe2x80x2-(6,7-Dichloro-3-thiophen-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine; 
Nxe2x80x2-(6,7-Difluoro-3-thiophen-2-yl-quinoxalin-2-yl)-N,N-dimethyl-butane-1,4-diamine; 
Nxe2x80x2-[6,7-Dichloro-3-(1H-indol-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine; 
Nxe2x80x2-(3-Benzo[b]thiophen-2-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine; 
N,N-Diethyl-Nxe2x80x2-(3-thiophen-2-yl-7-trifluoromethyl-quinoxalin-2-yl)-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-methyl-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine; 
Nxe2x80x2-(6,7-Dichloro-3-thiazol-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
Nxe2x80x2-(3-[2,2xe2x80x2]Bithiophenyl-5-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-chloro-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-methoxy-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-propyl-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-(3-Benzofuran-2-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine; 
Nxe2x80x2-[6,7-Dichloro-3-dibenzothiophen-4-yl-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine; 
[6,7-Dichloro-3-(5-phenyl-oxazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-(5-thiophen-2-yl-oxazol)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine; 
N-(6,7-Dichloro-3-pyridin-3-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethyl-cyclohexane-1,4-diamine;
N-(6,7-Dichloro-3-pyridin-4-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethyl-cyclohexane-1,4-diamine;
N-(6,7-Dimethoxy-3-pyridin-2-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethyl-cyclohexane-1,4-diamine;
N,N-Dimethyl-Nxe2x80x2-(3-pyridin-2-yl-7,8-dihydro-6H-cyclopenta[g]quinoxalin-2-yl)-cyclohexane-1,4-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-ethane-1,2-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-butane-1,4-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-pentane-1,5-diamine;
N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-pentane-1,5-diamine;
N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-hexane-1,6-diamine;
[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylsulfanyl)-propyl]-dimethylamine;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(3-morpholin4-yl-propyl)-amine;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(3-methoxypropyl)-amine;
Nxe2x80x2-1-[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylamino)-propyl]-Nxe2x80x2-1-methyl-propane-1,3-diamine;
2-{[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylamino)-propyl]-(2-hydroxy-ethyl)-amino}-ethanol;
{4-[4-(2-Chloro-phenyl)-piperidin-1-yl]-butyl-(6,7-dichloro-3-pyridin-2-yl-quinoxalin-2-yl)}amine;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(1-phenyl-4-piperidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-(1-ethyl-5-phenyl-imidazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-(1-phenyl-imidazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-[1-ethyl-5-(5-methyl-thiophene-2-yl)-imidazol-5-yl]-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine; and
[6,7-Dichloro-3-(1-phenyl-pyrazolo-5-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
or a pharmaceutically acceptable salt thereof.
A preferred compound of Formula II in the second aspect of the present invention is one wherein A is selected from the group consisting of: 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein
R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, or 
xe2x80x83wherein R3 and R3a are as defined above; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, an R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above,
halogen, or
alkoxy; and
R2a is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, and R6 are as defined above, or 
xe2x80x83wherein n, R5, and R6 are as defined above.
A more preferred compound of Formula II in the second aspect of the present invention is one wherein A is 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein
R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, or 
xe2x80x83wherein R3 and R3a are as defined above; and
R2a is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, R6 are as defined above, or 
xe2x80x83wherein n, R5, R6 are as defined above.
Another more preferred compound of Formula II in the second aspect of the present invention is one wherein 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein
R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, or R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or
R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are is as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b ere defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, or 
xe2x80x83wherein R3 and R3a are as defined above; and
R2a is CF3,
CCl3,
CBr3, or 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, and R6 are as defined above, or 
xe2x80x83wherein n, R5, and R6 are as defined above.
A most preferred compound of Formula II in the second aspect of the present invention is one wherein 
wherein R3, R3a, and R3b are each independently the same or different and are hydrogen,
alkyl,
aryl,
heteroaryl,
xe2x80x94OR4 wherein R4 is hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein
R5 and R6 are each the same or different and are hydrogen, alkyl, cycloalkyl, acetyl, or
R5 and R6 are taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 is as defined above and m is an integer of 2 to 5, 
xe2x80x83wherein n is zero or an integer of 1 and R7 and R8 are each independently the same or different and are hydrogen,
alkyl,
aryl,
aralkyl,
acetyl, or 
xe2x80x83wherein R5 and R6 are as defined above or R7 and R8 taken together to form a 5- to 7-membered ring optionally containing an oxygen atom or Nxe2x80x94R4 wherein R4 and m are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above, 
xe2x80x83wherein R7, R8, and n are as defined above,
xe2x80x94(CH2)nxe2x80x94SO2OR4 wherein R4 and n are as defined above,
xe2x80x94(CH2)nxe2x80x94CO2R4 wherein R4 and n are as defined above,
xe2x80x94CH2OR4 wherein R4 is as defined above,
halogen,
CF3,
CBr3,
CCl3, or
NO2; 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, 
xe2x80x83wherein R3 and R3a are as defined above, 
xe2x80x83wherein R3, R3a, and R3b are as defined above, or 
xe2x80x83wherein R3, R3a, and R3b are as defined above; and 
xe2x80x83wherein R10 is hydrogen and 
xe2x80x83wherein m, R5, and R6 are as defined above, or 
xe2x80x83wherein n, R5, R6 are as defined above.
Particularly valuable in the second aspect of the present invention is a compound selected from the group consisting of:
Nxe2x80x2-[6-Chloro-3-(2-pyridinyl)-2-quinoxalinyl]-N,N-diethyl-1,2-ethanediamine;
Nxe2x80x2-[7-Chloro-3-(2-pyridinyl)-2-quinoxalinyl]-N,N-diethyl-1,2-ethanediamine;
Nxe2x80x2-[6,7-Dichloro-3-(2-pyridinyl)-2-quinoxalinyl]-N,N-diethyl-1,2-ethanediamine;
6,7-Dichloro-3-(2-pyridinyl)-N-[3-(1-pyrrolidinyl)propyl]-2-quinoxalinamine;
6-Chloro-3-(2-pyridinyl)-N-[2-(1-pyrrolidinyl)ethyl]-2-quinoxalinamine;
7-Chloro-3-(2-pyridinyl)-N-[2-(1-pyrrolidinyl)ethyl]-2-quinoxalinamine;
Nxe2x80x2-[6,7-Dimethyl-3-(2-pyridinyl)-2-quinoxalinyl]-N,N-diethyl-1,2-ethanediamine;
6-Chloro-3-(2-pyridinyl)-N-[3-(1-pyrrolidinyl)propyl]-2-quinoxalinamine;
7-Chloro-3-(2-pyridinyl)-N-[3-(1-pyrrolidinyl)propyl]-2-quinoxalinamine;
Nxe2x80x2-[6,7-Dimethyl-3-(2-pyridinyl)-2-quinoxalinyl]-N,N-dimethyl-1,3-propanediamine;
Nxe2x80x2-[6-Chloro-3-(2-pyridinyl)-2-quinoxalinyl]-N,N-dimethyl-1,3-propanediamine;
Nxe2x80x2-[7-Chloro-3-(2-pyridinyl)-2-quinoxalinyl]-N,N-dimethyl-1,3-propanediamine;
6-Chloro-N-[4-(dimethylamino)cyclohexyl]-3-(2-pyridinyl)-2-quinoxalinamine;
7-Chloro-N-[4-(dimethylamino)cyclohexyl]-3-(2-pyridinyl)-2-quinoxalinamine;
2,6,7-Trimethyl-3-piperazin-1-yl-quinoxaline;
N,N-Dimethyl-Nxe2x80x2-(3-methyl-quinoxalin-2-yl)-propane-1,3-diamine;
2-Methyl-3-(4-methyl-piperazin-1-yl)-quinoxaline;
2-Ethyl-3-piperazin-1-yl-quinoxaline;
6,7-Dichloro-2-methyl-3-piperazin-1-yl-quinoxaline;
2-Phenyl-3-piperidin-1-yl-quinoxaline;
Benzyl-(3-phenyl-quinoxalin-2-yl)-amine;
Phenyl-(3-phenyl-quinoxalin-2-yl)-amine;
Methyl-(3-phenyl-quinoxalin-2-yl)-amine;
3-Phenyl-quinoxalin-2-ylamine;
2-Methyl-3-piperazin-1-yl-quinoxaline;
2-Methyl-3-piperidino-quinoxaline;
5-[4-(3-Methyl-quinoxalin-2-yl)-piperazin-1-yl]-pentan-1-ol;
N,N-Dimethyl-Nxe2x80x2-(3-methyl-quinoxalin-2-yl)-ethane-1,2-diamine;
N,N-Diethyl-Nxe2x80x2-(3-methyl-quinoxalin-2-yl)-ethane-1,2-diamine;
(3-Methyl-quinoxalin-2-yl)-(3-morpholin-4-yl-propyl)-amine;
N,N-Dimethyl-Nxe2x80x2-(3-phenyl-quinoxalin-2-yl)-propane-1,3-diamine;
3-Phenyl-quinoxalin-2-ylamine;
2-Methyl-3-pyrrolidin-1-yl-quinoxaline;
N-(1-Azabicyclo[2.2.2]octan-3-yl)-3-(2-pyridinyl)-2-quinoxalinamine;
N-[3-(1H-Imidazol-1-yl)propyl]-3-(2-pyridinyl)-2-quinoxalinamine;
N-[2-(1-Methyl-2-pyrrolidinyl)ethyl]-3-(2-pyridinyl)-2-quinoxalinamine;
1-[3-[[3-Pyridinyl)-2-quinoxalinamine]amino]propyl]-2-pyrrolidinone;
N-[4-(4-Morpholinyl)phenyl]-3-(2-pyridinyl)-2-quinoxalinamine;
N-(4-Piperidinylmethyl)-3-(2-pyridinyl)-2-quinoxalinamine;
N-[4-(Dimethylamino)phenyl]-3-(2-pyridinyl)-2-quinoxalinamine;
N-Methyl-N-[4-[[3-(2-pyridinyl)-2-quinoxalinyl]amino]phenyl]-acetamide;
N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethylcyclohexane-1,4-diamine;
N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-cyclohexane-1,4-diamine;
2-[1,4xe2x80x2]Bipiperidinyl-1xe2x80x2-yl-6,7-dichloro-3-pyridin-2-yl-quinoxaline;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(4-diethylaminomethylphenyl)-amine;
Nxe2x80x2-(6,7-Dichloro-3-furan-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
Nxe2x80x2-(6,7-Dichloro-3-thiophen-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine; 
Nxe2x80x2-(6,7-Difluoro-3-thiophen-2-yl-quinoxalin-2-yl)-N,N-dimethyl-butane-1,4-diamine; 
Nxe2x80x2-[6,7-Dichloro-3-(1H-indol-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine; 
Nxe2x80x2-(3-Benzo[b]thiophen-2-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine; 
N,N-Diethyl-Nxe2x80x2-(3-thiophen-2-yl-7-trifluoromethyl-quinoxalin-2-yl)-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-methyl-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine; 
Nxe2x80x2-(6,7-Dichloro-3-thiazol-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
Nxe2x80x2-(3-[2,2xe2x80x2]Bithiophenyl-5-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-chloro-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-methoxy-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-[6,7-Dichloro-3-(5-propyl-thiophen-2-yl)-quinoxalin-2-yl]-N,N-diethyl-butane-1,4-diamine;
Nxe2x80x2-(3-Benzofuran-2-yl-6,7-dichloro-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine; 
Nxe2x80x2-[6,7-Dichloro-3-dibenzothiophen-4-quinoxalin-2-yl)-N,N-diethyl-butane-1,4-diamine; 
[6,7-Dichloro-3-(5-phenyl-oxazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-(5-thiophen-2-yl-oxazol)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine; 
N-(6,7-Dichloro-3-pyridin-3-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethylcyclohexane-1,4-diamine;
N-(6,7-Dichloro-3-pyridin-4-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethylcyclohexane-1,4-diamine;
N-(6,7-Dimethoxy-3-pyridin-2-yl-quinoxalin-2-yl)-Nxe2x80x2,Nxe2x80x2-dimethylcyclohexane-1,4-diamine;
N,N-Dimethyl-Nxe2x80x2-(3-pyridin-2-yl-7,8-dihydro-6H-cyclopenta[g]quinoxalin-2-yl)-cyclohexane-1,4-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-ethane-1,2-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-propane-1,3-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-butane-1,4-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-pentane-1,5-diamine;
N-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-pentane-1,5-diamine;
Nxe2x80x2-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-N,N-dimethyl-hexane-1,6-diamine;
[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylsulfanyl)-propyl]-dimethylamine;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(3-morpholin-4-yl-propyl)-amine;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(3-methoxypropyl)-amine;
Nxe2x80x2-1-[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylamino)-propyl]-Nxe2x80x2-1-methyl-propane-1,3-diamine;
2-{[3-(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-ylamino)-propyl]-(2-hydroxy-ethyl)-amino}-ethanol;
{4-[4-(2-Chloro-phenyl)-piperidin-1-yl]-butyl-(6,7-dichloro-3-pyridin-2-yl-quinoxalin-2-yl)}amine;
(6,7-Dichloro-3-pyridin-2-yl-quinoxalin-2-yl)-(1-phenyl-4-piperidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-(1-ethyl-5-phenyl-imidazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-(1-phenyl-imidazol-2-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
[6,7-Dichloro-3-[1-ethyl-5-(5-methyl-thiophene-2-yl)-imidazol-5-yl]-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine; and
[6,7-Dichloro-3-(1-phenyl-pyrazolo-5-yl)-quinoxalin-2-yl]-(4-pyrrolidin-1-yl-butyl)-amine;
or a pharmaceutically acceptable salt thereof.
The compounds of Formula I and II are valuable receptor antagonists of IL-8.
The IL-8 chemokine inhibitory effects of compounds of the present invention were determined by the following procedures:
Compounds of Formula I and II were evaluated for their effect on chemotaxis using methodology known in the art, e.g., Carr M. W., Roth S. J., Luther E., Rose S. S., and Springer T. A., xe2x80x9cMonocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant.xe2x80x9d Proc. Natl. Acad Sci. USA, 1994;91:3652; Qin S., Larosa G., Campbell J. J. et al., xe2x80x9cExpression of MCP-1 and IL-8 receptors on subset on T-cells, and correlation with transendothelial chemotactic potential,xe2x80x9d Eur. J. Immu., 1996;26:640.
Briefly, freshly isolated human neutrophils were resuspended in chemotaxis buffer, which is made of one part of RPMI 1640 medium, one part of Medium 199, and 0.5% BSA. The cells were incubated with or without compounds for 5 minutes. Similarly, rhIL-8 was incubated in a separate plate, then transferred into lower chambers of chemotaxis plate. Neutrophils were added onto the top chamber. The plates were incubated at 37xc2x0 C. for 30 minutes. The top chamber was then removed and the plate frozen at xe2x88x9280xc2x0 C. for 30 minutes. After thawing, migrated cells were stained with Cytoquant Cell Proliferation Assay Kit (Molecular Probes No. C-7026) and quantitated by reading the plate on a fluorescent plate reader.
Compounds of Formula I and II were evaluated for their effect on calcium flux using methodology known in the art, e.g., Neote K., DiGregorio D., Mak J. Y., Horuk R., and Schall T. J., xe2x80x9cMolecular cloning, functional expression, and signaling characteristics of a Cxe2x80x94C chemokine receptor,xe2x80x9d Cell, 1993;72:415.
Briefly, human neutrophils were incubated with the fluorescence dye FLUO-3 for 1 hour. The cells were washed after this loading period, resuspended in HANKs buffer, and loaded into a 96-well plate. Compound was added to each well. After a 2-minute incubation period, the cells were stimulated with human IL-8 and the calcium flux response recorded and quantified.
The Table 1 shows the effect of a representative compound of the present invention on chemotaxis and calcium flux.
The compounds of Formula I and II may be obtained by applying synthetic methodology known in the art, such as, for example, Werbel L. et al., J. Med. chem., 1968;11:630; Moderhack D., et al., Chem. Ber., 1994:1633; Loriga M, et al., Farmaco, 1995;50(5):289; Chin. Chem. Lett., 1990;1(3):25; Shepard T. and Smith D. M., J. Chem. Soc., Perkin Trans I, 1987;3(501):11.
The procedures which may be used for the preparation of compounds 2 to 8 of Scheme 1 from compound 1 are described below.
Compounds of structure 4 in Scheme 1 are prepared by treating diamine 1 with the appropriate glyoxylate oxime in 20% to 40% H2SO4 at 50xc2x0 C. to 80xc2x0 C. for up to 2 days to give 2. Compound 3 is prepared by treatment of 2 with phosphorous oxychloride at reflux for up to 1 day. Treatment of 3 with two or more equivalents of the appropriate diamine in aromatic or ether solvents at reflux for up to 3 days gives 4. If one equivalent of diamine is used, treatment of one equivalent of an organic base or K2CO3 in aromatic solvents at reflux for up to 3 days is used to prepare 4 from 3.
Compounds of structure 5 are prepared by treating 3 with two or more equivalents of the corresponding thiol or amine in aromatic solvents at reflux for up to 3 days. If the acid salt of the thiol or amine is used, one or two equivalents of an organic base in aromatic solvents or ethers at reflux for up to 3 days may be used to prepare 5 from 3.
Compounds of structure 7 or 8 are prepared by treating 3 with 2 equivalents of the corresponding protected amine in aromatic solvents at reflux for up to 3 days to give 6. Compound 7 is prepared from 6 by treatment with concentrated mineral acid or gaseous HCl in aromatic solvent or alcohols at 0xc2x0 to room temperature for up to 1 day. Treatment of 7 with formalin and formic acid at 50xc2x0 C. to 100xc2x0 C. for up to 2 days gives 8. 
wherein Ar is Aryl or Pyridine and n=0 to 6;
R=Alkyl, alkoxy, halogen, or H;
R1=Alkyl, aryl, or H;
R2=Alkyl, aryl, or H;
X=Sulfur, oxygen, nitrogen, Nxe2x80x94Me. 
The procedure for the preparation of compound 2 to 8 of Scheme 2 are described below.
Compounds of structure 5 in Scheme 2 are prepared by treating diamine 1 with dialkyl oxalate at reflux (150-250xc2x0 C.) for up to 10 hours to give 2. Compounds 3 are prepared upon treatment of 2 with a bromination reagent, preferably PBr5 at 100xc2x0 C. to 200xc2x0 C. for up to 3 hours. The dibromide 3 is dissolved in diethyl ether or THF solvent and treated with two or more equivalents of the diamine 6 at 0xc2x0 C. to room temperature for up to 5 hours to give compound 4. Compounds of structure 5 are prepared by treating 4 with heterocyclic stannanes, 1-10% catalytic palladium catalyst, preferably Pd(PPh3)2Cl2, with 2-20% copper salt, such as CuI at 50xc2x0 C. to 100xc2x0 C. Additionally, compounds of structure 8 are prepared by reacting compounds 3 with ammonia followed by Stille-coupling reaction and alkylation as shown in Scheme 2.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or II or a corresponding pharmaceutically acceptable salt of a compound of Formula I or II.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as agents for the treatment of psoriasis, or atopic dermatitis, disease associated with pathological angiogenesis (i.e., cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, gastric ulcer, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, Alzheimer""s disease, graft versus host reaction, allograft rejections, or allergic diseases, the compounds utilized in the pharmaceutical method of this invention can be administered at the initial dosage of about 1 mg to about 100 mg per kilogram daily. A daily dose range of about 25 mg to about 75 mg per kilogram is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.